Chapter 6. Atherosclerosis in relation to cholelithiasis and cholesterolosis

Chapter 6. Atherosclerosis in relation to cholelithiasis and cholesterolosis Z. ZAHOfi Thefrequency of cholelithiasis and cholesterolosis was remarkably similar in Prague and Malmo subjects. When the possible effects of associated hypertension or diabetes mellitus were taken into account, subjects with cholelithiasis showed the same extent of raised and calcified lesions of the coronary arteries, the same prevalence oflarge myocardial scars, and the same distribution of heart weight as subjects without cholelithiasis. In general, they showed rather fewer raised and calcified lesions of the aorta, less coronary stenosis, and fewer fresh myocardial infarctions than subjects without cholelithiasis. Subjects with cholesterolosis were similar to those without this condition in respect of raised lesions of the aorta and coronary arteries. Men with cholesterolosis had slightly more aortic calcifica- tion and slightly less coronary calcification. Women with cholesterolosis had slightly less coronary stenosis than those without cholesterolosis. There was a slight tendency for those with cholesterolosis to show an increasedfrequency offresh myocardial infarction and large myocardial scars and to have a higher heart weight. Reports of the increased frequency of coronary heart disease (3) or atherosclerosis (10, 15) in sub- jects with cholelithiasis have not been confirmed by others (7, 16). These conflicting results and the rela- tionship of cholesterolosis of the gall bladder mu- cosa to atherosclerosis were clarified to some extent by analysis of the autopsy data from Malmo and Prague. ATHEROSCLEROSIS AND CHOLELITHIASIS Material and methods Information on cholelithiasis was obtained retro- spectively from the autopsy records from Malmo and Prague. Cholecystectomy was more frequent in Malmo (8 %) than in Prague (3 %). Since the opera- tion was nearly always performed for gallstones they were included in the calculation of the frequency of cholelithiasis (Table 15). Methods of evaluating atherosclerosis and myo- cardial lesions have been described in Chapter 1. The relationship between the presence of the disease and atherosclerosis was analysed as follows: 1. Subjects with and without cholelithiasis were compared for prevalence of atherosclerotic lesions in the aorta and the coronary arteries. 2. The same two groups of subjects were com- pared for extent of atherosclerosis in the average aorta and average coronary artery and for preva- lence of coronary stenosis and of myocardial and cerebrovascular lesions. 3. Subjects with hypertension and diabetes mel- litus were excluded from the two groups and analy- ses according to 1 and 2 above were then repeated. 4. Subjects with and without cholelithiasis were compared for thickness of subcutaneous fat and for body weight. Results The frequency of cholelithiasis increased with age in both sexes and it was significantly higher in women than in men (Table 15). It was similar in the separate age groups in Malmo and Prague even though gallstones seemed to appear earlier in Malmo. The overall frequency in male subjects over the age of 10 was 28% for Prague and 31% for Malmo; the corresponding figures for females were 51% and 52%. Prevalence. In general, no significant differences were found between subjects with and without chole- lithiasis as regards the prevalence of atherosclerotic BULL. WORLD HEALTH ORGAN., Vol. 53, 1976- 5313469 5 ZHZ. ZAHOR Table 1 5. Frequency of cholelithiasis and cholecystec- tomy (Malmo and Prague), by age and sex Frequency of Casesof cholelithiasisCases of caslecs-o and/orAge cholelithiasis tchcyso cholecys-group tectomytety (% of all deaths) Malmo Prague Malmo Prague Malmo Prague Males 10-19 - - - 0 0 20-29 3 - - - 6 0 30-39 4 2 - 5 7 40-49 20 9 14 3 15 17 50-59 92 50 25 7 21 17 60-69 246 163 50 23 29 31 70-79 269 215 29 17 35 40 80-89 94 80 6 6 42 36 90-99 15 6 1 - 62 55 Total 743 525 125 56 28 31 Females 10-19 1 - 5 0 20-29 4 - 2 - 19 0 30-39 11 2 4 1 28 27 40-49 24 9 14 1 24 15 50-59 107 59 30 7 39 36 60-69 274 206 59 30 53 51 70-79 371 382 89 32 61 55 80-89 139 281 27 6 60 59 90-99 16 22 - 2 57 60 Total 947 961 225 79 51 52 lesions in the abdominal aorta or left anterior de- scending coronary artery. No differences were found in the age-standardized averages for each town separately, and when subjects with hypertension and diabetes mellitus were excluded from the two groups this pattern did not change. There was a tendency for the prevalence of coronary stenosis to be lower among those with cholelithiasis than among those without, but this difference was not consistent or significant. Extent. As regards the extent of atherosclerotic lesions in the average aorta and average coronary artery in subjects with and without cholelithiasis, although there were occasional significant differences in some age groups no definite trend emerged. There was a suggestion that aortic atherosclerosis was slightly more extensive and coronary atherosclerosis slightly less extensive in the cholelithiasis group of subjects. There were no constant differences between the towns, whether subjects with hypertension and diabetes were or were not excluded from the two groups. The extent of raised and calcified lesions in the average aorta and coronary artery in the pooled 40-79-year age groups was compared with that in the low, standardized average, and high atheroscle- rosis groups. In men, raised aortic lesions were significantly more extensive in both the cholelithiasis and the non-cholelithiasis groups than in the cor- responding standardized average atherosclerosis group but significantly lower than in the high athero- sclerosis group. The ratio was somewhat higher for the cholelithiasis group, which thus seemed to have slightly more aortic raised lesions than the group without cholelithiasis. Women were similar to the standardized average group and the ratios for those with and without cholelithiasis did not differ. Aortic calcified lesions were slightly more extensive in both men and women in both groups than in the stan- dardized average groups. In men coronary raised lesions were significantly more extensive in the chole- lithiasis group than in the standardized average group, while in the non-cholelithiasis group they were similar to the standardized average group. In women they were similar in the cholelithiasis group to the standardized average group, while in the non- cholelithiasis group they were lower than in the standardized average group. The extent of calcified coronary lesions was higher in both men and women with and without cholelithiasis than in the corre- sponding standardized average groups and these differences were sometimes significant. The ratios for raised coronary lesions were somewhat higher in the cholelithiasis than in the non-cholelithiasis groups but the differences were only slight. When subjects with hypertension and diabetes were excluded from the cholelithiasis group, the extent of raised aortic lesions in men was similar to that of the standardized average group but in women it was less and not significantly different from that in the low atherosclerosis group. Raised coronary lesions in men were similar in extent to those in the standardized average group. In women, however, they were significantly lower than in the standard- 532 CHOLELITHIASIS AND CHOLESTEROLOSIS ized average group but higher than in the low atherosclerosis group. Calcified lesions in the aorta and the coronary arteries did not differ significantly in extent from those in the standardized average group. The prevalence of coronary stenosis and of myo- cardial lesions was studied both by 10-year age groups and in the pooled 40-79 year age group. Subjects with and without cholelithiasis did not differ significantly in prevalence of coronary stenosis in any single age group. Men showed a somewhat higher frequency than the standardized average group, irrespective of the presence of cholelithiasis, women showed somewhat lower prevalence than the corresponding standardized average group and this difference was significant in the non-cholelithiasis group. The ratios were similar and the prevalence of coronary stenosis thus did not vary with the presence of cholelithiasis. When subjects with hypertension and diabetes were excluded from the cholelithiasis group the slight difference found for women became larger and reached a significant level. The prevalence of fresh myocardial infarction did not differ significantly between subjects with and without cholelithiasis in the age-grouped material. When measured against the standardized average group the frequency of fresh myocardial infarction and of large myocardial scar showed the same features as in the cholelithiasis and non-cholelithiasis groups. In males the rates were higher than for the standardized average group and lower than for the high atherosclerosis group. In females the rates were lower than for the standardized average group. When subjects with hypertension or diabetes melli- tus were excluded from the cholelithiasis groups the rates for fresh myocardial infarction in males were similar to those for the standardized average group but those for large myocardial scar remained higher. The prevalence of cerebral haemorrhage did not differ in those with or without cholelithiasis but cerebral infarction was more common in almost all age groups among those with cholelithiasis than among those without. These differences were occa- sionally significant and persisted even when subjects with hypertension and diabetes mellitus were excluded. No constant trend emerged for differences in the extent of atherosclerosis and prevalence of coronary stenosis and myocardial lesions between the two towns. Table 16 shows the significant differences for the relation between cholelithiasis and body build, as Table 16. Differences in body weight and thickness of subcutaneous fat in subjects from Malmo and Prague Body weighta Thickness of Age group subcutaneous fata Malmo Prague Malmo Prague Males 30-39 NCb NCb C NC 40-49 C C C C 50-59 C C Cb C 60-69 C b C c C b C b 70-79 C Cd C Cd 80-89 NC C c C Cb Females 30-39 NC b NC NC C 40-49 NC C NC NC 50-59 NC C NC C 60-69 Cd Cd Cd Cd 70-79 C c C c C Cd 80-89 Cc cc C cc a a C " indicates that the value for body weight or fat was greater in subjects with cholelithiasis; "NC" indicates that the value for body weight or fat was greater in subjects without cholelithiasis. b p < 0.05. c p < 0.01. d p < 0.001. measured by body weight or thickness of subcutane- ous fat. There seemed to be an association between the presence of cholelithiasis and the thickness of subcutaneous fat and body weight, especially in the Prague material, in which the differences were often highly significant. The differences were most evident in the seventh, eighth, and ninth decades. Discussion The frequency of cholelithiasis has been variously assessed in the literature. Surprisingly, the frequency was almost identical in Malmo and Prague and it seems to be among the highest that has been re- ported. It also corresponds well with the frequency reported from Malmo by Sternby (16). There are conflicting reports concerning the poss- ible association between atherosclerosis and chole- lithiasis. Thus Gross compared a group of 357 au- topsy cases without gallstones with 220 cases with gallstones and of these two groups 5200 and 72%, 533 Z. ZAHOk respectively, were judged as positive for " ather- oma" (9). The author concluded that the two condi- tions were associated but unfortunately gave no detailed information about either the definition of " atheroma" or the age and sex distribution of the material. Other reports, e.g., that of Curtius et al. (5), also lack clear-cut definitions, and the mate- rial studied does not seem to be representative of any defined age and sex group ofthe population. The same applies to the reports by Sjovall & Wihan (15) and Henschen (10), who showed that subjects with chole- lithiasis had more atherosclerosis than those without. One of the first studies to fulfil the requirements for more reliable studies of the association between cholelithiasis and atherosclerosis was carried out by Sternby (16); the study showed no definite trend in the relation between the presence or absence of cholelithiasis and the degree of atherosclerosis in either sex. These conclusions were corroborated by our findings. As early as the beginning of this century Babcock drew attention to an apparent association between gallstones and heart disease (2). A number of authors have been interested in this problem since then. Breyfolge (3), for example, reported a positive association but Cleland (4) did not. Friedman (7) dealt with this question very critically and pointed out the possibility of drawing erroneous conclusions in assessing an association between these diseases as a result of chance, selection, or diagnostic difficul- ties. He concluded that there was probably either no association or only a modest one. Only obesity appeared to be a factor associated with both cor- onary heart disease and gall bladder disease. We did not find any definite association between cholelithiasis and atherosclerotic lesions in the cor- onary arteries. There was, however, a tendency to an increased frequency of myocardial lesions and of cerebral infarction. This is in accord with the results of Friedman, who did not find any evidence of " strong association between cholelithiasis and cor- onary heart disease" while admitting " some basis for a weak association " (7). Gross found a positive association between chole- lithiasis and obesity, but on the basis of the mean weight of all cases from 25 years upwards without taking age groups into account. Since the body weight tends to decrease in the highest age groups, whereas, on the other hand, the frequency of chole- lithiasis rises, these results could be strongly influ- enced by an unequal age distribution. Nevertheless, there appears to be a true positive association be- tween the presence of cholelithiasis and the body weight (7,12,15). The results of this study were in accord with such a hypothesis, although this was more evident in the Czech than in the Swedish autopsy series. Some studies, however, have not shown any differences in body weight between women with and without gallstones (14). An incidental finding was that the frequency of gall bladder carcinoma was much higher in those with gallstones than in those without. In the 50-89 age group the mean frequency of gall bladder carci- noma in those with gallstones was 2.3 % and 4.3 %, respectively, for men and women; in those without gallstones the corresponding figures were 0.5 % and 1.0%. ATHEROSCLEROSIS AND CHOLESTEROLOSIS The analysis regarding a possible association be- tween cholesterolosis of the gall bladder mucosa and atherosclerosis was performed in the same way as for cholelithiasis. Results The frequency of cholesterolosis of the gall blad- der mucosa differed to some extent in the age and sex groups between Malmo and Prague (Table 17). These differences may, however, be influenced by the rather small number of subjects in some groups. Moreover, the diagnosis of cholesterolosis was made macroscopically and routinely and the initial stages of cholesterolosis might therefore not have been recorded. There was, however, a very similar fre- quency in the whole material from each sex and from both towns. No differences were observed in the prevalence of atherosclerotic aortic and coronary lesions between subjects with and without cholesterolosis. Nor were any significant differences found in the extent of lesions in the average aorta and coronary artery, although there was a suggestion that men with cholesterolosis had slightly more raised lesions. No definite inter-town differences were found, and the exclusion of hypertensives and diabetics from the two groups did not change the pattern. The extent of lesions in those with and without cholesterolosis was also studied in the combined 40-79-year age group and compared with that in the three reference atherosclerosis groups. Raised aortic lesions were less extensive in men in the standardized average group than in those with or without choles- 534 CHOLELITHIASIS AND CHOLESTEROLOSIS Table 17. Frequency of cholesterolosis in Malmo and Prague a Malmo Prague Malmoand Prague Age group 1 2 % 1 2 % 1 2 % Males 10-19 30 0 0 10 0 0 40 0 0 20-29 51 0 0 16 0 0 67 0 0 30-39 81 4 5 28 1 4 109 5 5 40-49 212 11 5 68 4 6 280 15 5 50-59 530 31 6 319 22 7 849 53 6 60-69 986 92 9 577 42 7 1563 134 9 70-79 829 80 10 557 35 6 1386 115 8 80-89 230 18 8 236 21 9 466 39 8 90-99 25 0 0 11 0 0 36 0 0 All cases 2974 236 7.9 1822 125 6.9 4796 361 7.5 Females 10-19 20 0 0 7 0 0 27 0 0 20-29 30 2 7 8 1 13 38 3 8 30-39 49 3 6 10 2 20 59 5 8 40-49 142 10 7 65 8 12 207 18 9 50-59 324 24 7 175 18 10 499 42 8 60-69 567 56 10 436 40 9 1003 96 10 70-79 668 59 9 717 46 6 1385 105 8 80-89 249 14 6 480 15 3 729 29 4 90-99 28 3 11 38 1 3 66 4 6 All cases 2077 171 8.2 1936 131 6.8 4013 302 7.5 a In each group of 3 columns, column (1) indicates the total number of subjects minus the number of cases of cholecystectomy, column (2) gives the number of cases of cholesterolosis, and the third column shows the percentage of cases of cholesterolosis. terolosis. In women no such differences were found. The ratios were, however, similar, thus showing no certain difference between the two cholesterolosis groups. Coronary raised lesions varied in a similar way; there was a tendency for men with choles- terolosis to have slightly more of these lesions than men without, whereas in women no such difference was observed. The extent of calcified lesions in the aorta and coronary arteries varied somewhat with sex but showed no consistent trend. Men with cholesterolosis had a higher prevalence of coronary stenosis than those without, whereas in women the finding was the reverse. These differences remained when hypertensives and diabetics were excluded. The prevalence of myocardial lesions, especially of fresh myocardial infarction, was higher in men with cholesterolosis than in those without; this was also the case for women but the differences between the two groups were rather small. No differences in the prevalence of cerebrovascular lesions were found between those with and without cholesterolosis. The relationship between the presence and ab- sence of cholesterolosis and body build (measured as body weight or thickness of subcutaneous fat) was also studied; the differences between those with and 535 3 vZ. ZAHOR Table 18. Differences in body weight and thickness of subcutaneous fat in subjects from Malmo and Prague with and without cholesterolosis of the gall bladder mucosa Body weight a Subcutaneous fat a Age group Malmo Prague Malmo Prague Males 20-29 30-39 C NC C b NC 40-49 NC NC C NCc 50-59 C C C C 60-69 Cd C Cd C 70-79 cc C cc C 80-89 C C NC C Females 20-29 NC NC NC NC 30-39 NC C NC C 40-49 C C Cc NC 50-59 NC C NC NC 60-69 c C C C 70-79 NC C b NC NC 80-89 C C NC C a C" indicates that the value for body weight or fat was greater in subjects with cholelithiasis; "NC" indicates that the value for body weight or fat was greater in subjects without cholelithiasis. b p < 0.05. c p < 0.01. d p < 0.001. without cholesterolosis are shown in Table 18. The differences were slight. Men from Malmo with chole- sterolosis were fatter, sometimes significantly so, than those without, whereas Prague men showed no such difference, or only a tendency in that direction. Women from Prague tended to have higher body weight but not more subcutaneous fat and the findings for Malmo women were unclear. Discussion A comprehensive review of the problem of choles- terolosis was made by Salmenkivi (13). The fre- quency of cholesterolosis is reported to vary greatly, in surgical and in autopsy series (5-39 % and 5-46 %, respectively). The frequency in this study was within these limits. The frequency did not increase with age; on the contrary, women from Prague in the highest age groups had a lower frequency of choles- terolosis than those in the middle age groups. This was in contrast to the finding for cholelithiasis, which was shown to increase with age. No significant differences in the frequency of cholesterolosis were noted between males and females except in a few age groups. This was also in contrast to the finding that women have a higher frequency of cholelithiasis than men. These results may be taken as an indication that there is no certain relationship between the presence of cholelithiasis and cholesterolosis. There are also some studies of autopsy material that show a negative correlation between cholelithiasis and cholesterolosis (1, 6, 16). This finding was also con- firmed by Zschoch (17), who found cholesterolosis without gallstones twice as often as cholesterolosis in combination with gallstones in an autopsy series. This difference was statistically significant. The find- ing of no association between the presence of choles- terolosis and atherosclerosis in this study is in complete agreement with the findings reported by others (1, 6, 16). Regarding the relationship between cholesterolosis and obesity, Judd & Mentzer (11) reported that cholesterolosis was present in 70% of subjects weighing more than 95 kg, while Feldman & Feldman (6) did not find any relation between obe- sity and cholesterolosis. The results of this study were partly contradictory, which may be explained by the fact that the recording of this condition was taken from routine autopsy material. However, it seems unlikely that there is a strong relationship between obesity and cholesterolosis. UME CHAPITRE 6. ATHEROSCLEROSE, CHOLELITHIASE ET CHOLESTE'ROLOSE La frequence de la cholelithiase et de la cholesterolose presente une similitude remarquable chez les habitants de Prague et de Malmo. Lorsque l'on tient compte des effets possibles d'une association a l'hypertension art& rielle ou au diabete sucre, on trouve chez les sujets por- teurs de cholelithiase le meme degre de lesions saillantes et de calcifications des arteres coronaires, la meme prevalence de vastes cicatrices myocardiques, et la meme distribution du poids du cceur que chez ceux qui n'ont pas de cholelithiase. En general, les premiers presentent 536 CHOLELITHIASIS AND CHOLESTEROLOSIS 537 plutot moins de 1lsions saillantes ou calcifiees de I'aorte, moins de stenoses coronaires et moins d'infarctus myo- cardiques recents que les seconds. Sous le rapport des lesions saillantes de I'aorte et des arteres coronaires, les malades atteints de cholesterolose sont comparables a ceux qui ne presentent pas cette affection. Les hommes atteints de cholesterolose ont un peu plus de calcifications dans l'aorte et un peu moins dans les coronaires. Les femmes atteintes de cholesterolose presentent des stenoses coronaires legerement moins nombreuses que celles qui n'ont pas de cholesterolose. Pour celles qui en sont atteintes, on note une 16gere tendance 'a 'augmentation de frequence des infarctus myocardiques recents, des vastes cicatrices du myocarde, et de 1'elevation du poids du cceur. REFERENCES 1. AHLIN, T. Bruns' Beitr. klin. Chir., 167: 555 (1938). 2. BABCOCK, R. H. J. Am. med. 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